Multifocal Papillary Thyroid Cancer Increases the Risk of Central Lymph Node Metastasis

Abstract

Background:

Papillary thyroid cancer (PTC) is the most common thyroid malignancy, with a strong predilection for lymph node metastasis, most commonly to the central neck compartment (level VI). Few studies have evaluated lymph node metastasis in multifocal PTC, and the role of level VI dissection in the management of PTC remains controversial. This retrospective analysis evaluated the rate of level VI lymph node positivity in multifocal PTC, as compared with unifocal disease, in order to inform surgical decision making better.

Methods:

Patients with PTC who underwent total or hemi-thyroidectomy plus level VI lymph node dissection at the authors' institution between January 2008 and June 2014 were included (N=227). The number and laterality of PTC foci, lymphovascular invasion (LVI), extrathyroidal extension (ETE), and positive/total number of level VI lymph nodes were recorded. Fisher's exact test was used to determine univariate associations, and multivariate analysis was done by logistical regression.

Results:

There was an association between the number of PTC foci and level VI node positivity (p<0.001), with an odds ratio (OR) of 2.355 in patients with three or more tumor foci (p=0.026). The OR for central neck metastasis was 1.088 with each additional focus of PTC (p=0.018). The risk of level VI node positivity in the presence of one or two foci was only 19%, with no appreciable difference between one and two foci. This risk increased in the presence of between three and nine foci (38%), and 10 or more foci (88%). Level VI node positivity was associated with ETE (p<0.001), LVI (p<0.001), and size of the largest focus (p<0.001). There was no association between level VI lymph node positivity and male sex (p=0.089), bilaterality (p=0.276), or age (p=0.076).

Conclusions:

There is a significant association between multifocal PTC and level VI lymph node positivity, increasing proportionally with the number of foci. These findings recognize multifocality as a sign of tumor aggressiveness, as evidenced by a higher propensity for lymph node metastasis.

Introduction

A global increase in the incidence of thyroid cancer has been reported over recent years (1). Papillary thyroid cancer (PTC) is the most common type of thyroid malignancy, accounting for >85% of all cases. Despite a very favorable prognosis for patients with this malignancy, the long-term mortality rate can be as high as 10% (2,3).

PTC often presents with multifocal tumors, which can be unilateral or bilateral. Multifocality is thought to arise through intraglandular spread of tumor cells from a primary focus (4). Other studies have suggested that each focus arises independently, as a result of distinct genetic mutations, on a background of environmental/host susceptibility (5 –7). Importantly, multifocality is associated with higher rates of disease recurrence and poorer prognosis compared with unifocal disease (2,8).

It is well-established that PTC has a strong propensity for lymph node metastasis. Up to one third of patients have clinically detectable lymph node involvement on initial presentation (9). Of patients with no detectable nodal disease on examination, an estimated 80% will have micrometastatic lymph node disease on postoperative pathologic examination (10). Lymph node metastasis in PTC is known to increase the chance of local disease recurrence (11). Although many studies have identified nodal disease as a poor prognostic factor for long-term patient survival (12 –15), this remains controversial (16). Lymph node metastasis in PTC follows a predictable pattern. Most commonly, tumor cells metastasize to lymph nodes of the central neck compartment (level VI), followed by those of the lateral neck (levels II, III, and IV) (17). Rarely, “skip” lesions can occur, whereby metastases appear in the lateral neck compartments while sparing the central neck (18 –20). Lymph nodes of the level VI compartment are bordered by the hyoid bone superiorly, suprasternal notch inferiorly, and the carotid sheaths laterally (21). The American Thyroid Association (ATA) recommends therapeutic level VI dissections in patients with clinical evidence of lymph node involvement (22). However, the role for prophylactic level VI lymph node dissection remains largely controversial because of a lack of randomized clinical trials (9).

To date, few studies have assessed the effect of multifocality on the pathological and clinical features of PTC (8). This article focuses on the relationship between the number of PTC foci and metastasis to level VI lymph nodes.

Materials and Methods

Data collection

Ethics approval was obtained from the Research Ethics Board at the authors' institution. All patients with a pathologically confirmed diagnosis of PTC who underwent a thyroidectomy (partial or total) and a level VI lymph node dissection between January 2008 and June 2014 were included. The criteria for performing a level VI lymph node dissection included all patients with a fine-needle aspirate (FNA) result showing malignancy or suspicious for malignancy (SFM), as per the Bethesda System (23). Central neck dissection was also performed for patients with FNA results showing atypia of unknown significance (AUS) or suspicious for neoplasm (SFN) in the presence of specific negative predictive factors. These included severe nuclear atypia on FNA, a family history of thyroid cancer, and syndromes predisposing for PTC such as Gardner's Syndrome and Cowden Syndrome. A database was generated containing patient demographics, number and laterality of each focus, extrathyroidal spread, margin status, lymphovascular invasion (LVI), and number of positive/total lymph nodes.

Multifocal disease was defined as the presence of two or more foci of PTC. For patients with micropapillary carcinoma, each focus was recorded separately. Bilateral disease was defined as the presence of PTC foci in the right and left lobes of the thyroid gland. The size of the largest focus of PTC was used for analysis. Margins, LVI, and extrathyroidal extension (ETE) were considered positive if recorded as such for any of the foci. For patients who underwent a completion thyroidectomy, pathology results from the completion surgery were compiled with those from the primary surgery. Complete data sets were not available for all patients due to differences in reported parameters on pathology reports.

Statistical analysis

Statistical analysis was performed using IBM SPSS Statistics for Windows v21 (IBM Corp., Armonk, NY). Univariate analysis was performed using Fisher's exact tests for categorical variables, Student's t-tests for normally distributed data, and Mann–Whitney U-tests for continuous variables that were not normally distributed. Logistical regression was used for multivariate analysis.

Results

A total of 340 patients were diagnosed with PTC between 2008 and 2014 at the authors' institution. Of these, 227 underwent a thyroidectomy plus a level VI lymph node dissection and were included in the study. The average age was 56.1 years, and 162 (71%) were female. The average size of the largest nodule was 2.2 cm (range 0.02–9.0 cm; median 1.7 cm). In patients with multifocal disease, the average size of the nondominant nodule(s) was 0.6 cm (range 0.01–9.5 cm; median 0.3 cm). Multifocal PTC was reported in 142 patients (63%), of whom 97 (68%) had bilateral disease. Of the patients with multifocal disease, 53 (37%) had two foci of disease, 64 (45%) had between three and nine foci, while 25 (18%) had 10 or more foci. ETE was reported in 44/221 (20%) patients, and LVI was seen in 47/222 (22%) patients (Table 1). Metastasis to level VI lymph nodes was seen in 152/227 (63%) patients. In 16/227 (7%) patients, no level VI lymph nodes were identified on pathology postoperatively. Among patients with positive central neck disease, the average number of lymph nodes harvested, as part of a level VI neck dissection, was 7.9 (range 1–30; median 7). The mean number of positive lymph nodes was 5 (range 1–25; median 4; Table 1).

Table 1.

Characteristics of the Study Population

Variable	Value (%)
Age
Average (years)	56.1
Sex
Male	65/227 (29)
Female	162/227 (71)
Size of largest focus
Average (cm)	2.2
Median (cm)	1.7
Size of nondominant foci
Average (cm)	0.6
Median (cm)	0.3
Focality
Unifocal	85/227 (37)
Multifocal disease	142/227 (63)
2 foci	53/142 (37)
3–9 foci	64/142 (45)
≥10 foci	25/142 (18)
Bilateral disease	96/142 (68)
Level VI metastasis	152/227 (70)
Level VI lymph nodes
Average harvested	7.9
Median harvested	7.0
Average positive	5.0
Median positive	4.0
ETE	44/221 (20)
LVI	47/222 (22)

ETE, extrathyroidal extension; LVI, lymphovascular invasion.

The association was investigated between several factors pertaining to the patient and disease, with level VI lymph node metastasis (Table 2). The association between male sex and level VI positivity was not significant in the study population (p=0.089); 27/65 (41%) male patients with PTC had positive level VI lymph nodes compared with 48/162 (30%) female patients. Fifty-six of 142 (39%) patients with multifocal PTC had positive central neck nodes compared with 19/85 (22%) patients with unifocal disease (p<0.001), showing a significant association between multifocality and central neck metastasis. Fifteen of 45 (33%) patients with unilateral, multifocal disease had nodal metastases compared with 41/96 (43%) patients with bilateral, multifocal disease (p=0.276). These data show no significant association between bilateral PTC and level VI nodal positivity. In patients with ETE, 32/44 (73%) had positive level VI lymph nodes compared with 42/177 (24%) patients with no ETE. Similarly, 56/77 (72%) patients with LVI had central neck metastasis compared with 18/145 (12%) patients with no LVI. These data demonstrate a significant association between LVI and ETE (p<0.001) with level VI positivity. Increasing size of the largest focus was significantly associated with central neck positivity (p<0.001). However, there was no significant correlation between increasing age and level VI lymph node positivity in the study population (p=0.076).

Table 2.

Univariate Analysis of Factors Associated with Level VI Lymph Node Metastasis

Variable	+ Level VI/total (%)	p-Value
Sex
Male	27/65 (41)	0.089
Female	48/162 (30)
Focality
Multifocal	56/142 (39)	<0.001
Unifocal	19/85 (22)
Laterality (if multifocal)
Bilateral	41/96 (43)	0.276
Unilateral	15/46 (33)
ETE
ETE	32/44 (73)	<0.001
No ETE	42/177 (24)
LVI
LVI	56/77 (72)	<0.001
No LVI	18/145 (12)
Increasing size of largest focus	—	<0.001
Increasing age	—	0.760

The effect of the number of PTC foci on level VI lymph node metastasis was further examined (Table 3). Nineteen of 85 (22%) patients with unifocal PTC had level VI lymph node metastases. Similarly, 10/53 (19%) patients with two foci of PTC were found to have positive lymph nodes. The proportion of patients with positive level VI nodes almost doubled in the group with between three and nine foci, where 24/64 (38%) patients were found to be positive. In patients with 10 or more PTC foci, 22/25 (88%) were found to have positive lymph nodes in level VI.

Table 3.

Risk of Level VI Lymph Nodes Positivity Based on the Number of PTC Foci

Number of foci	Number/total (%)
Unifocal	19/85 (22)
Multifocal
2 foci	10/53 (19)
3–9 foci	24/64 (38)
≥10 foci	22/25 (88)

PTC, papillary thyroid cancer.

The odds ratio (OR) for central neck metastasis was determined by logistic regression (Tables 4 and 5). Controlling for age, sex, size of the largest focus, ETE, and LVI, there was a significantly increased OR of 1.088 (p=0.018) for central neck metastasis with each additional focus of PTC (Table 4). Using the same model, the OR for metastasis to level VI lymph nodes was significantly increased with ETE (OR=3.126, p=0.022) and LVI (OR=8.052, p<0.001). The OR with increasing age, male sex, and size of the largest focus were 0.986, 1.407, and 1.048, respectively, and were nonsignificantly associated with metastasis (p>0.05). The OR for level VI positivity in patients with three or more foci of cancer was also evaluated. Using this model, a significantly increased OR of 2.355 (p=0.026) for level VI positivity was observed (Table 5). Similarly, the OR for level VI lymph node metastasis was significantly increased with ETE (OR=3.258, p=0.016) and LVI (OR=8.478, p<0.001). The OR with increasing age, male sex, and size of the largest focus were 0.986, 1.407, and 1.048, respectively, and were nonsignificantly associated with metastasis (p>0.05). Similar results were obtained when the analysis was repeated after excluding patients with no harvested lymph nodes in level VI dissection (data not shown).

Table 4.

Multivariate Analysis of Association of Level VI Lymph Node Metastasis with Additional Foci of PTC

	Level VI metastasis
Variable	Odds ratio (OR)	p-Value
Each additional focus of PTC	1.088	0.018
Age	0.986	0.296
Male sex	1.407	0.406
Size of largest focus	1.048	0.639
ETE	3.126	0.022
LVI	8.052	<0.001

Table 5.

Multivariate Analysis of Association of Level VI Lymph Node Metastasis with Multifocal PTC

	Level VI metastasis
Variable	Odds ratio (OR)	p-Value
Multifocality (≥3 foci)	2.355	0.026
Age	0.980	0.422
Male sex	1.391	0.353
Size of largest focus	1.057	0.591
ETE	3.258	0.016
LVI	8.478	<0.001

Discussion

In this study, the relationship was investigated between the number of PTC foci and tumor metastasis to the central neck compartment. Multifocality has been reported in 18–87% of patients with PTC (4), and was seen in 63% of patients in the present study. The current results show that the risk of level VI lymph metastasis increases proportionally with the number of tumor foci. There was no appreciable difference in level VI lymph node metastasis in patients with one (22%) and two foci (19%). In comparison, level VI lymph node positivity doubled in the presence of between three and nine foci (38%), and quadrupled in the presence of 10 or more foci (88%). Multivariate analysis showed a significantly increased OR of 1.088 for lymph node metastasis to the central compartment with each additional focus of PTC. Furthermore, a significantly increased OR of 2.355 was observed for metastasis in patients with three or more foci of PTC. These findings identify multifocality in PTC as an indicator of tumor aggressiveness, manifesting in a higher propensity for locoregional metastasis.

Very few studies have investigated the effect of multifocality on lymph node metastasis. Most recently, Qu et al. (8) investigated the effect of multifocality on prognosis in patients with one, two, or three or more PTC foci undergoing thyroidectomy. It was found that a larger number of foci, especially three or more, significantly increased the chance of recurrence and death. Central neck metastasis increased proportionally with increasing numbers of foci, and was reported at 74.9%, 78%, and 82.4%, respectively, among the groups. Although a similar trend was observed in the current data set, the percentage of patients with central neck metastasis who had two (19%) and between three and nine (38%) foci was smaller in comparison. This could be attributed to earlier detection and intervention in the study population.

Univariate analysis identified increasing size of tumor foci, multifocality, ETE, and LVI as significant predictors of level VI lymph node metastasis in the study population. Multivariate analysis further showed that multifocality, ETE, and LVI conferred a significantly increased OR for central neck metastasis. These findings are consistent with previously published studies identifying risk factors for level VI metastasis in PTC (24 –26). There was no significant association between age or bilaterality and central neck positivity in the study population. Similarly, it has been suggested that there is no significant link between age or bilaterality and lymph node metastasis (25,27). Interestingly, an increasing number of PTC foci was recently found to be associated with younger age, further correlating multifocality with biological aggressiveness (8). Clinically, multifocal papillary carcinomas of the thyroid gland are very often diagnosed incidentally on pathology following a total or hemithyroidectomy (28). Given the negative impact of multifocal disease on recurrence and patient survival, total thyroidectomy may offer a more effective option for complete disease eradication, especially in patients with three or more tumor foci (8).

The most commonly reported incidence of lymph node involvement in the literature is 50%, with up to 30% of tumors smaller than 0.3 cm showing microscopic nodal disease (26,29). This emphasizes the strong predisposition for lymph node metastasis in PTC. In this study, 70% of patients had positive level VI lymph nodes. Several reports have identified lymph node metastasis as a poor prognostic factor in PTC (8,12 –15). However, this remains controversial, as other studies suggest that lymph node positivity has no effect on long-term patient prognosis because of the indolent nature of PTC (16,30). The role for prophylactic central neck dissection is highly controversial, and has been the focus of many studies over the past decades (9). In experienced hands, the addition of a level VI lymph node dissection to total thyroidectomy confers no additional risk of injury to the recurrent laryngeal nerve or of permanent hypocalcemia (31). In patients diagnosed with multifocal PTC on pathology following a hemithyroidectomy, the addition of a level VI lymph node dissection to a completion thyroidectomy may be considered, especially in patients with three or more tumor foci.

This study, like any other, has its limitations. Patients selected for a level VI lymph node dissection had features suggestive of a more aggressive clinical disease. Although this may have generated a selection bias, it had no bearing on the correlation between multifocality and central lymph node metastasis that was found in this study. As a retrospective chart review, this investigation does not shed light on patient prognosis/survival in relation to the number of tumor foci or level VI lymph node positivity. The number of patients included represents a relatively small cohort in a single center. To ensure a larger and more representative sample, multicenter studies are required. Lastly, the impact of the subtype of PTC on multifocality and lymph node metastasis needs further delineation.

In conclusion, it was observed that multifocality increases the risk of metastasis to the central neck compartment in PTC. Lymph node metastasis doubled in the presence of between three and nine foci and quadrupled in the presence of 10 or more foci when compared with unifocal and bifocal disease. Central neck metastasis was also significantly related to LVI, ETE, and size of the largest focus. The present data highlight that the presence of multiple foci in PTC is an indicator of disease aggressiveness, seen by a higher tendency for spread to the central neck compartment.

Footnotes

Author Disclosure Statement

All authors have no conflicts of interest to disclose.

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